Abstract
The purpose of this study was to improve the bioavailability of carbamazepine (CBZ), a poorly water-soluble antiepileptic drug, via modified-release amorphous solid dispersions (mr-ASD) by a thin film freezing (TFF) process. Three types of CBZ-mr-ASD with immediate-, delayed-, and controlled-release properties were successfully prepared with HPMC E3 (hydrophilic), L100-55 (enteric), and cellulose acetate (CA, lipophilic), defined as CBZ-ir-ASD, CBZ-dr-ASD, and CBZ-cr-ASD, respectively. A dry granulation method was used to prepare CBZ-mr-ASD capsule formulations. Various characterization techniques were applied to evaluate the physicochemical properties of CBZ-mr-ASD and the related capsules. The drug remained in an amorphous state when encapsulated within CBZ-mr-ASD, and the capsule formulation progress did not affect the performance of the dispersions. In dissolution tests, the preparations and the corresponding dosage forms similarly showed typical immediate-, delayed-, and controlled-release properties depending on the solubility of the polymers. Moreover, single-dose 24 h pharmacokinetic studies in rats indicated that CBZ-mr-ASD significantly enhanced the oral absorption of CBZ compared to that of crude CBZ. Increased oral absorption of CBZ was observed, especially in the CBZ-dr-ASD formulation, which showed a better pharmacokinetic profile than that of crude CBZ with 2.63- and 3.17-fold improved bioavailability of the drug and its main active metabolite carbamazepine 10,11-epoxide (CBZ-E).
Highlights
The gastrointestinal (GI) tract is the most convenient and popular route used for drug administration in the clinic, with better patient compliance and fewer costs [1]
The present study demonstrated that modified-release amorphous solid dispersions (mr-amorphous solid dispersions (ASD)) prepared by thin film freezing (TFF) can be used to enhance the oral bioavailability of compounds with low dissolution rates and poor PK characteristics
Three kinds of CBZ-mr-ASD with immediate, delayed, and controlled-release properties were successfully prepared with HPMC E3, L100-55, and CA by a TFF process
Summary
The gastrointestinal (GI) tract is the most convenient and popular route used for drug administration in the clinic, with better patient compliance and fewer costs [1]. Most marketed drugs are available in oral dosage forms. The dissolution of these drugs in GI fluids is a prerequisite for GI absorption and clinical efficacy. Approximately 40% of drugs on the market and up to 70% of new chemical entities for drug development exhibit poor water solubility [2,3]. This poor water solubility results in additional problems. A low drug dissolution rate will limit drug bioavailability after oral administration, especially for biopharmaceutical classification system class II (BCS II) drugs, which have poor water solubility and high permeability [4,5]. Enhancement of the dissolution rate plays a crucial role in improving the oral bioavailability of BCS II drugs
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